XENPOZYME Powder for solution for infusion Ref.[50126] Active ingredients: Olipudase alfa

Xenpozyme treatment should be supervised by a healthcare professional experienced in the management of ASMD or other inherited metabolic disorders. Xenpozyme infusion should be administered by a healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious systemic hypersensitivity reactions.

Posology

The rapid metabolism of accumulated sphingomyelin (SM) by olipudase alfa generates pro-inflammatory breakdown products, which may induce infusion-associated reactions and/or transient liver enzyme elevations. A dose escalation regimen can minimise the majority of these adverse events (see section 5.3).

Xenpozyme dose is based on the actual body weight for patient with a body mass index (BMI) ≤30 or an optimal body weight for patient with a BMI >30 (see section for patients with a BMI >30).

Adults

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.1 mg/kg* for adults (also see missed doses subsection for additional guidance) and subsequently, the dose should be increased according to the dose escalation regimen presented in Table 1.

Table 1. Dose escalation regimen in adults:

^* Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI >30, an optimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

^* Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI >30, an optimal body weight will be used as described below.

Paediatric population

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.03 mg/kg* for paediatric patients, and the dose should be subsequently increased according to the dose escalation regimen presented in Table 2.

Table 2. Dose escalation regimen in paediatric patients:

^* Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI >30, an optimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

^* Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI >30, an optimal body weight will be used as described below.

Patients with BMI >30

In adult and paediatric patients with a body mass index (BMI) >30, the body weight that is used to calculate the dose of Xenpozyme is estimated via the following method (for dose escalation and maintenance phases).

Body weight (kg) to be used for dose calculation = 30 × (actual height in m)2

Example:

For a patient with:

BMI of 38
body weight of 110 kg
height of 1.7 m.

The dose to be administered will be calculated using a body weight of 30 × 1.72 = 86.7 kg.

Missed doses

A dose is considered missed when not administered within 3 days of the scheduled date. When a dose of Xenpozyme is missed, the next dose should be administered as described below as soon as possible. Thereafter, administrations should be scheduled every 2 weeks from the date of the last administration.

During the dose escalation phase:

• If 1 infusion is missed: the last tolerated dose should be administered, before resuming dose escalation according to the regimen in adults (Table 1) or in paediatric patients (Table 2).
• If 2 consecutive infusions are missed: 1 dose level lower than the last tolerated dose (using a minimal dose of 0.3 mg/kg) should be administered, before resuming dose escalation according to Table 1 or Table 2.
• If 3 or more consecutive infusions are missed: dose escalation should be resumed at 0.3 mg/kg according to Table 1 or Table 2. At the next scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg, that dose should be administered twice as per Table 1 and Table 2.

During the maintenance phase:

• If 1 maintenance infusion is missed: the maintenance dose should be administered and the treatment schedule adjusted accordingly.
• If 2 consecutive maintenance infusions are missed: 1 dose below the maintenance dose (i.e. 2 mg/kg) should be administered. Then for subsequent infusions, the maintenance dose (3 mg/kg) every 2 weeks should be administered.
• If 3 or more consecutive maintenance infusions are missed: dose escalation should be resumed at 0.3 mg/kg according to Table 1 or Table 2.

Monitoring of transaminase level

Transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels should be obtained prior to treatment initiation and monitored during any dose escalation phases (see section 4.4). If the pre-infusion transaminase levels are elevated above baseline and >2 times the upper limit of normal (ULN), the Xenpozyme dose can be adjusted (prior dose repeated or reduced) or treatment can be temporarily withheld in accordance with the degree of transaminase elevation. If a patient requires a dose adjustment or treatment interruption, treatment re-initiation should follow the dose escalation regimen described in Table 1 and Table 2 for adult and paediatric patients, respectively, and recommendations in case of missed doses (see missed doses section).

Special populations

Elderly patients

No dose adjustment is recommended for patients over the age of 65 (see section 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

Renal impairment

No dose adjustment is recommended in patients with renal impairment (see section 5.2).

Method of administration

Xenpozyme is for intravenous use only. Infusions should be administered in a stepwise manner preferably using an infusion pump.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

After reconstitution and dilution, the solution is administered as an intravenous infusion. The infusion rates must be incrementally increased during the infusion only in the absence of infusion-associated reactions (in case of infusion-associated reactions, see section 4.4.). The infusion rate and duration of infusion (+/- 5 min) for each step of infusion are detailed in Table 3 and Table 4.

Table 3. Infusion rates and duration of infusion in adult patients:

hr: hour; min: minute; NA: Not applicable

Table 4. Infusion rates and duration of infusion in paediatric patients:

hr: hour; min: minute; NA: Not applicable

Signs and symptoms of infusion-associated reactions (IARs), such as headache, urticaria, pyrexia, nausea and vomiting, and other signs or symptoms of hypersensitivity should be monitored during the infusion. Depending on the symptom severity, the infusion may be slowed, paused or discontinued and appropriate medical treatment initiated as needed.

In case of severe hypersensitivity and/or anaphylactic reaction, treatment with Xenpozyme should be discontinued immediately (see section 4.4).

At the end of infusion (once the syringe or infusion bag is empty), the infusion line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection using the same infusion rate as the one used for the last part of the infusion.

Home infusion during maintenance phase

Home infusion under the supervision of a healthcare professional may be considered for patients on maintenance dose and who are tolerating their infusions well. The decision to have patients moved to home infusion should be made after evaluation and recommendation by the prescribing physician. Appropriate medical support, including personnel trained in emergency measures, should be readily available when Xenpozyme is administered. If anaphylactic or other acute reactions occur, immediately discontinue the Xenpozyme infusion, initiate appropriate medical treatment and seek the attention of a physician. If severe hypersensitivity reactions occur, subsequent infusions should only occur in a setting where resuscitation measures are available. Dose and infusion rates should remain constant while at home, and should not be changed without supervision of the prescribing physician. In case of missed doses or delayed infusion, the prescribing physician should be contacted.

There is no known specific antidote for Xenpozyme overdose. For the management of adverse reactions linked to Xenpozyme, see sections 4.4 and 4.8.

Unopened vials:

48 months.

Reconstituted medicinal product:

After reconstitution with sterile water for injection, chemical, physical and microbiological in-use stability has been demonstrated for up to 24 hours at 2-8°C or 12 hours at room temperature (up to 25°C).

From a microbiological point of view, the reconstituted medicinal product should be used immediately. If not used for dilution immediately, in-use storage times and conditions prior to dilution are the responsibility of the user and should normally not be longer than 24 hours at 2°C-8°C or 12 hours at room temperature (up to 25°C).

Diluted medicinal product:

After dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, chemical, physical and microbiological in-use stability has been demonstrated between 0.1 mg/mL and 3.5 mg/mL for 24 hours at 2-8°C, and up to 12 hours (including infusion time) when stored at room temperature (up to 25°C).

From a microbiological point of view, the diluted medicinal product should be used immediately. If not used immediately after dilution, in-use storage times and conditions are the responsibility of the user and should normally not be longer than 24 hours at 2°C to 8°C followed by 12 hours (including infusion time) at room temperature (up to 25°C).

Store in a refrigerator (2°C-8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

20 mg of powder for concentrate for solution for infusion in a vial (Type I glass) with a siliconized chlorobutyl-elastomer lyophilization stopper, and an aluminum seal with a plastic flip-off cap.

Each pack contains 1, 5, 10 or 25 vials. Not all pack sizes may be marketed.

Vials are for single use only.

Infusions should be administered in a stepwise manner preferably using an infusion pump.

Preparation of the dosing solution

The powder for concentrate for solution for infusion must be reconstituted with sterile water for injection, diluted with sodium chloride 9 mg/mL (0.9%) solution for injection and then administered by intravenous infusion.

The reconstitution and dilution steps must be completed under aseptic conditions. Filtering devices should not be used at any time during the preparation of the infusion solution. Avoid foaming during reconstitution and dilution steps.

1) Determine the number of vials to be reconstituted based on the individual patient’s weight and the prescribed dose. Patient weight (kg) × dose (mg/kg) = patient dose (in mg). Patient dose (in mg) divided by 20 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

2) Remove the required number of vials from refrigeration and set aside for approximately 20 to 30 minutes to allow them to reach room temperature.

3) Reconstitute each vial by injecting 5.1 mL of sterile water for injection into the vial using a slow drop-wise addition technique to the inside wall of the vial.

4) Tilt and roll each vial gently. Each vial will yield a 4 mg/mL clear, colorless solution.

5) Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. Xenpozyme solution should be clear and colorless. Any vials exhibiting opaque particles or discoloration should not be used.

6) Withdraw the volume of reconstituted solution, corresponding to the prescribed dose, from the appropriate number of vials and dilute with sodium chloride 9 mg/mL (0.9%) solution for injection, in a syringe or infusion bag depending on the volume of infusion (see Table 12 for the recommended total infusion volume based on patients age and/or weight).

Table 12. Recommended infusion volumes:

For variable final volumes of infusion based on body weight in paediatric patients (see Table 12):

• Prepare an infusion solution at 0.1 mg/mL by adding 0.25 mL (1 mg) of the reconstituted solution prepared in step 3) and 9.75 mL of sodium chloride 9 mg/mL (0.9%) solution for injection in an empty 10 mL syringe.
• Calculate the volume (mL) required to obtain the patient dose (mg).

Example: 0.3 mg ÷ 0.1 mg/mL = 3 mL

Dilution instructions for 5 mL ≤ total volume ≤20 mL using a syringe:

• Inject the required volume of the reconstituted solution slowly to the inside wall of the empty syringe.
• Add slowly the sufficient quantity of sodium chloride 9 mg/mL (0.9%) solution for injection to obtain the required total infusion volume (avoid foaming within the syringe).

Dilution instructions for a total volume ≥50 mL using an infusion bag:

• Empty infusion bag:
  • Inject slowly the required volume of the reconstituted solution from step 3) in the appropriate size sterile infusion bag.
  • Add slowly the sufficient quantity of sodium chloride 9 mg/mL (0.9%) solution for injection to obtain the required total infusion volume (avoid foaming within the bag).
• Pre-filled infusion bag:
  • Withdraw from the infusion bag pre-filled with sodium chloride 9 mg/mL (0.9%) solution for injection the volume of normal saline to obtain a final volume as specified in Table 12.

**Add slowly the required volume of the reconstituted solution from step 3) into the infusion bag (avoid foaming within the bag).

7) Gently invert the syringe or the infusion bag to mix. Do not shake. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution.

8) The diluted solution must be filtered through an in-line low protein-binding 0.2 μm filter during administration.

9) After the infusion is complete, the infusion line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection using the same infusion rate as the one used for the last part of the infusion.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.